耐药癫痫动物模型的研究进展_Journal of Epilepsy

Authors：

刘钱坤 ,  陈阳美

重庆医科大学附属第二医院神经内科（重庆 400010）;

Corresponding author：

陈阳美, Email: chenym1997@cqmu.edu.cn

Keywords：

癫痫; 耐药癫痫; 药物筛选; 动物模型

DOI：

10.7507/2096-0247.202204006

Video：

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耐药癫痫的治疗依然是神经科重大难题。在研究耐药癫痫病理生理改变及筛选抗癫痫发作药物时，所选择的癫痫模型起到十分重要的作用。本文就近年来国内外的耐药癫痫模型研究进展作一比较，8种耐药癫痫的依次为：3-巯基丙酸模型、海马海人酸模型、锂-匹罗卡品模型、角膜点燃模型、单纯杏仁核点燃模型、抗苯妥英钠杏仁核点燃模型、苯巴比妥耐药癫痫模型、抗拉莫三嗪杏仁核点燃模型。这些模型中，前三种为单纯化学点燃模型，之后两种主要为单纯电点燃模型，最后三种为化学刺激加电点燃模型。本文文从设备条件、造模过程、成功率、耐药评估、海马病理改变等多方面归纳对比，以便学者根据实验室条件和实验目的选用合适的耐药癫痫模型。

Citation： 刘钱坤, 陈阳美. 耐药癫痫动物模型的研究进展. Journal of Epilepsy, 2022, 8(4): 331-337. doi: 10.7507/2096-0247.202204006 Copy

1.	Sander JW, Shorvon SD. Epidemiology of the epilepsies. Journal of Neurology Neurosurgery & Psychiatry, 1996, 61(5): 433-443.
2.	Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
3.	Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
4.	Jr engel J. The current place of epilepsy surgery. Curr Opin Neurol, 2018, 31(2): 192-197.
5.	Maguire MJ, Jackson CF, Marson AG, et al. Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP). Cochrane Database Syst Rev, 2016, 7(7).
6.	Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol, 2016, 12(2): 106-116.
7.	Stables JP, Bertram E, Dudek FE, et al. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the Nih/ninds/aes Models Ii Workshop. Epilepsia, 2010, 44(12): 1472-1478.
8.	Enrique A, Goicoechea S, Castao R, et al. New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice. Epilepsy Research, 2017, 129: 8-16.
9.	Riban V, Bouilleret V, Pham-lê BT, et al. Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience, 2002, 112(1): 101-111.
10.	方子妍, 吴逢春, 陈树达, 等. 苯妥英钠耐药性颞叶内侧癫痫大鼠模型的构建. 癫痫杂志, 2019, 5(1): 21-25.
11.	许兰, 王丽琨, 周鑫, 等. 两种耐药性颞叶癫痫模型海马硬化及苔藓纤维发芽的对比. 贵州医科大学学报, 2019, 44(10): 1145-1150.
12.	唐太峰, 伍国锋. 耐苯巴比妥钠及苯妥英钠杏仁核点燃大鼠癫痫模型的制作. 贵州医科大学学报, 2016, 41(6): 671-674.
13.	陆海美, 谢美娟, 李姗, 等. 6 Hz角膜点燃耐药癫痫小鼠模型改良及3种中药方剂的作用. 药学学报, 2018, 53(7): 1048-1053.
14.	Jiang W, Du B, Chi Z, et al. Preliminary explorations of the role of mitochondrial proteins in refractory epilepsy: some findings from comparative proteomics. Journal of Neuroscience Research, 2007, 85(14): 3160-3170.
15.	Rocha L. Effects of high frequency electrical stimulation and r-verapamil on seizure susceptibility and glutamate and gaba release in a model of phenytoin-resistant seizures. Neuropharmacology, 2011, 61(4): 807-814.
16.	Zeng K, Wang X, Wang Y, et al. Enhanced synaptic vesicle traffic in hippocampus of phenytoin-resistant kindled rats. Neurochemical Research, 2009, 34(5): 899-904.
17.	Potschka H, Volk HA, Löscher W. Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats. Neuroreport, 2004, (10): 1657-1661.
18.	Volk HA, Löscher W. Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of p-glycoprotein compared with rats with drug-responsive seizures. Brain, 2005, 128(Pt 6): 1358-1368.
19.	Bethmann K, Fritschy JM, Brandt C, et al. Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy. Neurobiol Dis, 2008, 31(2): 169-187.
20.	Volk HA, Arabadzisz D, Fritschy JM, et al. Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis, 2006, 2(3): 633-646.
21.	Metcalf CS, Huff J, Thomson KE, et al. Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model. Epilepsia Open, 2019, 4(3): 452-463.
22.	Zhang C, Zuo Z, Kwan P, et al. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human p-glycoprotein. Epilepsia, 2011, 52(10): 1894-1904.
23.	Chen C, Zhou H, Guan C, et al. Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: a microdialysis study in rats. Pharmacology Research & Perspectives, 2020, 8(2): e00575.
24.	Nagaya Y, Nozaki Y, Takenaka O, et al. Investigation of utility of cerebrospinal fluid drug concentration as a surrogate for interstitial fluid concentration using microdialysis coupled with cisternal cerebrospinal fluid sampling in wild-type and mdr1a(-/-) rats. Drug Metabolism and Pharmacokinetics, 2016, (1): 57-66.
25.	Baraban SC, Löscher W. What new modeling approaches will help us identify promising drug treatments? Adv Exp Med Biol, 2014, 813: 283-294.
26.	Guillemain I, Kahane P, Depaulis A. Animal models to study aetiopathology of epilepsy: what are the features to model? Epileptic Disord, 2012, 14(3): 217-225.
27.	Klein S, Bankstahl M, Löscher W. Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. Neuropharmacology, 2015, 9: 53-62.
28.	Wang L, Shi J, Wu G, et al. Hippocampal low-frequency stimulation increased SV2A expression and inhibited the seizure degree in pharmacoresistant amygdala-kindling epileptic rats. Epilepsy Res, 2014, (9): 1483-1491.
29.	Toman JEP. Neuropharmacologic considerations in psychic seizures. Neurology, 1951, 1(6): 444-460.
30.	Löscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure, 2011, 20(5): 359-368.
31.	Albertini G, Walrave L, Demuyser T, et al. 6hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c‐fos immunoreactivity throughout the brain. Epilepsia, 2018, 59(1): 67-78.
32.	Florek-luszczki M, Wlaz A, Kondrat-wrobel MW, et al. Effects of win 55, 212-2 (a non-selective cannabinoid cb1 and cb2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6hz psychomotor seizure model. Journal of Neural Transmission, 2014, (7): 707-715.
33.	Matagne A, Klitgaard H. Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res, 1998, 31(1): 59-71.
34.	Leclercq K, Matagne A, Kaminski RM. Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model. Epilepsy Res, 2014, 108(4): 675-683.
35.	Rowley NM, White HS. Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: correlation with other seizure and epilepsy models. Epilepsy Res, 2010, 92(2): 163-169.
36.	Barker-haliski ML, Vanegas F, Mau MJ, et al. Acute cognitive impact of antiseizure drugs in naive rodents and corneal-kindled mice. Epilepsia, 2016, 57(9): 1386-1397.
37.	Barker-haliski ML, Johnson K, Billingsley P, et al. Validation of a preclinical drug screening platform for pharmacoresistant epilepsy. Neurochem Res, 2017, 42(7): 1904-1918.
38.	Remigio GJ, Loewen JL, Heuston S, et al. Corneal kindled C57BL/6 mice exhibit saturated dentate gyrus long-term potentiation and associated memory deficits in the absence of overt neuron loss. Neurobiol Dis, 2017, 105: 221-234.
39.	Loewen JL, Barker-haliski ML, Dahle EJ, et al. Neuronal injury, gliosis, and glial proliferation in two models of temporal lobe epilepsy. J Neuropathol Exp Neurol, 2016, 75(4): 366-378.
40.	Koneval Z, Knox KM, White HS, et al. Lamotrigine-resistant corneal-kindled mice: a model of pharmacoresistant partial epilepsy for moderate-throughput drug discovery. Epilepsia, 2018, 59(6): 1245-1256.
41.	Goddard GV, Mcintyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol, 1969, 25(3): 295-330.
42.	Löscher W. Animal models of drug-resistant epilepsy. Novartis Found Symp, 2002, 243: 149-166.
43.	Löscher Wr W. Animal models of intractable epilepsy. Prog Neurobiol, 1997, 53(2): 239-258.
44.	Lösche S, eds. Models of seizures and epilepsy. Elsevier, San Diego, 2006: 551-567.
45.	Töllner K, Wolf S, Löscher W, et al. The anticonvulsant response to valproate in kindled rats is correlated with its effect on neuronal firing in the substantia nigra pars reticulata: a new mechanism of pharmacoresistance. J Neurosci, 2011, 31(45): 16423-16434.
46.	Brandt C, Glien M, Potschka H, et al. Epileptogenesis and neuropathology after different types of status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala in rats. Epilepsy Res, 2003, 50(1): 83-103.
47.	Brandt C, Volk HA, Löscher W. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia, 2004, 45(12): 1488-1497.
48.	Bethmann K, Brandt C, Löscher W. Resistance to phenobarbital extends to phenytoin in a rat model of temporal lobe epilepsy. Epilepsia, 2007, 48(4): 816-826.
49.	Brandt C, Löscher W. Antiepileptic efficacy of lamotrigine in phenobarbital-resistant and -responsive epileptic rats: a pilot study. Epilepsy Res, 2014, 108(7): 1145-1157.
50.	Löscher W, Brandt C. High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy. Epilepsia, 2010, 51(1): 89-97.
51.	Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia, 2013, 54(s2): 33-40.
52.	Kwan P, Brodie MJ. Early identification of refractory epilepsy. The New England Journal of Medicine, 2000, 342(5): 314-319.
53.	Gastens AM, Brandt C, Bankstahl JP, et al. Predictors of pharmacoresistant epilepsy: pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy. Epilepsia, 2008, 49(10): 1759-1776.
54.	Löscher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res, 2016, 126: 157-184.
55.	Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med, 2004, 10(7): 685-692.
56.	Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3): 281-294.
57.	Klitgaard H, Matagne A, Gobert J, et al. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. European Journal of Pharmacology, 1998, 353(2): 191-206.
58.	Barton ME, White HS. The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression. Epilepsy Res, 2004, 59(1): 1-12.
59.	Klein BD, Jacobson CA, Metcalf CS, et al. Evaluation of cannabidiol in animal seizure models by the epilepsy therapy screening program (ETSP). Neurochem Res, 2017, 42(7): 1939-1948.
60.	Srivastava AK, Alex AB, Wilcox KS, et al. Rapid loss of efficacy to the antiseizure drugs lamotrigine and carbamazepine: a novel experimental model of pharmacoresistant epilepsy. Epilepsia, 2013, 54(7): 1186-1194.

1. Sander JW, Shorvon SD. Epidemiology of the epilepsies. Journal of Neurology Neurosurgery & Psychiatry, 1996, 61(5): 433-443.
2. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
3. Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
4. Jr engel J. The current place of epilepsy surgery. Curr Opin Neurol, 2018, 31(2): 192-197.
5. Maguire MJ, Jackson CF, Marson AG, et al. Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP). Cochrane Database Syst Rev, 2016, 7(7).
6. Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol, 2016, 12(2): 106-116.
7. Stables JP, Bertram E, Dudek FE, et al. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the Nih/ninds/aes Models Ii Workshop. Epilepsia, 2010, 44(12): 1472-1478.
8. Enrique A, Goicoechea S, Castao R, et al. New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice. Epilepsy Research, 2017, 129: 8-16.
9. Riban V, Bouilleret V, Pham-lê BT, et al. Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience, 2002, 112(1): 101-111.
10. 方子妍, 吴逢春, 陈树达, 等. 苯妥英钠耐药性颞叶内侧癫痫大鼠模型的构建. 癫痫杂志, 2019, 5(1): 21-25.
11. 许兰, 王丽琨, 周鑫, 等. 两种耐药性颞叶癫痫模型海马硬化及苔藓纤维发芽的对比. 贵州医科大学学报, 2019, 44(10): 1145-1150.
12. 唐太峰, 伍国锋. 耐苯巴比妥钠及苯妥英钠杏仁核点燃大鼠癫痫模型的制作. 贵州医科大学学报, 2016, 41(6): 671-674.
13. 陆海美, 谢美娟, 李姗, 等. 6 Hz角膜点燃耐药癫痫小鼠模型改良及3种中药方剂的作用. 药学学报, 2018, 53(7): 1048-1053.
14. Jiang W, Du B, Chi Z, et al. Preliminary explorations of the role of mitochondrial proteins in refractory epilepsy: some findings from comparative proteomics. Journal of Neuroscience Research, 2007, 85(14): 3160-3170.
15. Rocha L. Effects of high frequency electrical stimulation and r-verapamil on seizure susceptibility and glutamate and gaba release in a model of phenytoin-resistant seizures. Neuropharmacology, 2011, 61(4): 807-814.
16. Zeng K, Wang X, Wang Y, et al. Enhanced synaptic vesicle traffic in hippocampus of phenytoin-resistant kindled rats. Neurochemical Research, 2009, 34(5): 899-904.
17. Potschka H, Volk HA, Löscher W. Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats. Neuroreport, 2004, (10): 1657-1661.
18. Volk HA, Löscher W. Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of p-glycoprotein compared with rats with drug-responsive seizures. Brain, 2005, 128(Pt 6): 1358-1368.
19. Bethmann K, Fritschy JM, Brandt C, et al. Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy. Neurobiol Dis, 2008, 31(2): 169-187.
20. Volk HA, Arabadzisz D, Fritschy JM, et al. Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis, 2006, 2(3): 633-646.
21. Metcalf CS, Huff J, Thomson KE, et al. Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model. Epilepsia Open, 2019, 4(3): 452-463.
22. Zhang C, Zuo Z, Kwan P, et al. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human p-glycoprotein. Epilepsia, 2011, 52(10): 1894-1904.
23. Chen C, Zhou H, Guan C, et al. Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: a microdialysis study in rats. Pharmacology Research & Perspectives, 2020, 8(2): e00575.
24. Nagaya Y, Nozaki Y, Takenaka O, et al. Investigation of utility of cerebrospinal fluid drug concentration as a surrogate for interstitial fluid concentration using microdialysis coupled with cisternal cerebrospinal fluid sampling in wild-type and mdr1a(-/-) rats. Drug Metabolism and Pharmacokinetics, 2016, (1): 57-66.
25. Baraban SC, Löscher W. What new modeling approaches will help us identify promising drug treatments? Adv Exp Med Biol, 2014, 813: 283-294.
26. Guillemain I, Kahane P, Depaulis A. Animal models to study aetiopathology of epilepsy: what are the features to model? Epileptic Disord, 2012, 14(3): 217-225.
27. Klein S, Bankstahl M, Löscher W. Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. Neuropharmacology, 2015, 9: 53-62.
28. Wang L, Shi J, Wu G, et al. Hippocampal low-frequency stimulation increased SV2A expression and inhibited the seizure degree in pharmacoresistant amygdala-kindling epileptic rats. Epilepsy Res, 2014, (9): 1483-1491.
29. Toman JEP. Neuropharmacologic considerations in psychic seizures. Neurology, 1951, 1(6): 444-460.
30. Löscher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure, 2011, 20(5): 359-368.
31. Albertini G, Walrave L, Demuyser T, et al. 6hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c‐fos immunoreactivity throughout the brain. Epilepsia, 2018, 59(1): 67-78.
32. Florek-luszczki M, Wlaz A, Kondrat-wrobel MW, et al. Effects of win 55, 212-2 (a non-selective cannabinoid cb1 and cb2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6hz psychomotor seizure model. Journal of Neural Transmission, 2014, (7): 707-715.
33. Matagne A, Klitgaard H. Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res, 1998, 31(1): 59-71.
34. Leclercq K, Matagne A, Kaminski RM. Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model. Epilepsy Res, 2014, 108(4): 675-683.
35. Rowley NM, White HS. Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: correlation with other seizure and epilepsy models. Epilepsy Res, 2010, 92(2): 163-169.
36. Barker-haliski ML, Vanegas F, Mau MJ, et al. Acute cognitive impact of antiseizure drugs in naive rodents and corneal-kindled mice. Epilepsia, 2016, 57(9): 1386-1397.
37. Barker-haliski ML, Johnson K, Billingsley P, et al. Validation of a preclinical drug screening platform for pharmacoresistant epilepsy. Neurochem Res, 2017, 42(7): 1904-1918.
38. Remigio GJ, Loewen JL, Heuston S, et al. Corneal kindled C57BL/6 mice exhibit saturated dentate gyrus long-term potentiation and associated memory deficits in the absence of overt neuron loss. Neurobiol Dis, 2017, 105: 221-234.
39. Loewen JL, Barker-haliski ML, Dahle EJ, et al. Neuronal injury, gliosis, and glial proliferation in two models of temporal lobe epilepsy. J Neuropathol Exp Neurol, 2016, 75(4): 366-378.
40. Koneval Z, Knox KM, White HS, et al. Lamotrigine-resistant corneal-kindled mice: a model of pharmacoresistant partial epilepsy for moderate-throughput drug discovery. Epilepsia, 2018, 59(6): 1245-1256.
41. Goddard GV, Mcintyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol, 1969, 25(3): 295-330.
42. Löscher W. Animal models of drug-resistant epilepsy. Novartis Found Symp, 2002, 243: 149-166.
43. Löscher Wr W. Animal models of intractable epilepsy. Prog Neurobiol, 1997, 53(2): 239-258.
44. Lösche S, eds. Models of seizures and epilepsy. Elsevier, San Diego, 2006: 551-567.
45. Töllner K, Wolf S, Löscher W, et al. The anticonvulsant response to valproate in kindled rats is correlated with its effect on neuronal firing in the substantia nigra pars reticulata: a new mechanism of pharmacoresistance. J Neurosci, 2011, 31(45): 16423-16434.
46. Brandt C, Glien M, Potschka H, et al. Epileptogenesis and neuropathology after different types of status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala in rats. Epilepsy Res, 2003, 50(1): 83-103.
47. Brandt C, Volk HA, Löscher W. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia, 2004, 45(12): 1488-1497.
48. Bethmann K, Brandt C, Löscher W. Resistance to phenobarbital extends to phenytoin in a rat model of temporal lobe epilepsy. Epilepsia, 2007, 48(4): 816-826.
49. Brandt C, Löscher W. Antiepileptic efficacy of lamotrigine in phenobarbital-resistant and -responsive epileptic rats: a pilot study. Epilepsy Res, 2014, 108(7): 1145-1157.
50. Löscher W, Brandt C. High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy. Epilepsia, 2010, 51(1): 89-97.
51. Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia, 2013, 54(s2): 33-40.
52. Kwan P, Brodie MJ. Early identification of refractory epilepsy. The New England Journal of Medicine, 2000, 342(5): 314-319.
53. Gastens AM, Brandt C, Bankstahl JP, et al. Predictors of pharmacoresistant epilepsy: pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy. Epilepsia, 2008, 49(10): 1759-1776.
54. Löscher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res, 2016, 126: 157-184.
55. Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med, 2004, 10(7): 685-692.
56. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3): 281-294.
57. Klitgaard H, Matagne A, Gobert J, et al. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. European Journal of Pharmacology, 1998, 353(2): 191-206.
58. Barton ME, White HS. The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression. Epilepsy Res, 2004, 59(1): 1-12.
59. Klein BD, Jacobson CA, Metcalf CS, et al. Evaluation of cannabidiol in animal seizure models by the epilepsy therapy screening program (ETSP). Neurochem Res, 2017, 42(7): 1939-1948.
60. Srivastava AK, Alex AB, Wilcox KS, et al. Rapid loss of efficacy to the antiseizure drugs lamotrigine and carbamazepine: a novel experimental model of pharmacoresistant epilepsy. Epilepsia, 2013, 54(7): 1186-1194.

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